The focus of this research project is to perform a clinical evaluation of a new treatment strategy for men with castration resistant prostate cancer (CRPC) through the administration of Bipolar Androgen Therapy (BAT) consisting of monthly injections of sufficient testosterone to induce a rapid rise and then fall in serum testosterone from supraphysiologic to near-castrate levels over a treatment cycle. In the current treatment paradigm for recurrent CRPC, men are treated with increasingly more potent androgen deprivation therapies (ADT). The chronic exposure to ADT leads to therapeutic resistance, reduced quality of life and excess morbidity due to development of a castration-induced metabolic syndrome. Therapeutic resistance is due to the ability of prostate cancer cells to adaptively auto-regulate the expression of the androgen receptor (AR) and its variants to sufficient levels to maintain AR signaling in a chronically low androgen microenvironment. Besides its role in transcription, AR has been demonstrated to be a DNA licensing factor that plays a critical role in replication and must be degraded as the cell goes through cycle. Lack of AR degradation due to over- stabilization by supraphysiologic testosterone inhibits DNA re-licensing resulting in death in the subsequent cell cycle. Thus, the rationale for BAT therapy is that adaptive overexpression of AR by CRPC cells becomes a therapeutic liability that can be exploited through the administration of supraphysiologic doses of testosterone. The significance of the BAT approach proposed in this Project is that is has the potential to break resistance to ADT. Of further importance, BAT may also improve quality of life and functional capacity and minimize the morbidity from the metabolic syndrome produced by chronic ADT. The BAT strategy proposed in the project is supported by preclinical mechanistic studies and data from a pilot clinical study. This study demonstrated that BAT could be safely administered to men with minimal to moderate metastatic burden that were progressing on chronic ADT. BAT induced PSA declines in the majority of treated patients. To further evaluate BAT as a new treatment paradigm for CRPC the following Specific Aims are proposed in this Project: (1) Perform a Phase II clinical trial testing the safety and efficacy of BAT in men with progressive CRPC. This trial will confirm the results from the pilot study in a larger cohort of patients and test the abiity of BAT to re- sensitize CRPC cells to ADT and second-line hormone therapies abiraterone and enzalutamide. (2) Evaluate adaptive autoregulation of AR during BAT through quantification of AR transcripts in circulating tumor cells. The goal of this Aim is to evaluate levels of AR and AR variants in circulating tumor cells to support the hypothesis that BAT disrupts adaptive auto-regulation of AR. (3) Develop plasma DNA biomarkers to evaluate response to BAT. The goal of this Aim is to use whole exome sequencing and droplet digital PCR of circulating tumor DNA in plasma to identify somatic mutations within an individual patient's cancer to produce a set of personalized biomarker that can potentially be used to predict and/or monitor response to BAT.